Six patients with jejunostomies and residual jejunal lengths of 105 to 250 cm took the same food and water each day for eight study days. In random order, three methods of salt replacement were tested, each over 48 hours, against a period without added salt. During the three test periods the patients took 120 mmol of sodium chloride daily, as salt in gelatine capsules, as an isotonic glucose electrolyte (280 mOsmol/kg; 30 kcal) solution, and as a glucose polymer (Maxijul) solution (280 mOsmol/kg; 200 kcal). The daily stomal output remained constant for each patient during the four test periods but varied between patients from 0.60 to 2.84 kg (daily intestinal fluid balance 0.74-2.61 kg). Without a salt supplement, three patients lost more sodium from the stoma than they took in by mouth (-25, -94, and -101 mmol/day) and the mean sodium balance for all six subjects was -16 mmol (range -101 to 79) daily. Extra salt was absorbed with each form of supplement (p less than 0.05); no patient with the glucose electrolyte solution (mean 96, range 0 to 226 mmol), but one patient with the glucose-polymer solution (mean 96, range -25 to 164 mmol) and two with the salt capsules (mean 66, range -8 to 145 mmol) were in negative balance. Two patients vomited with the salt capsules. There was only a small increase in energy absorption (mean 115 kcal) with the glucose polymer solution compared with the glucose electrolyte solution. A sipped glucose electrolyte solution seems to be the optimal mode of sodium replacement in patients with a high output jejunostomy.

Acetorphan is an orally active inhibitor of enkephalinase (EC 3.4.24.11) with antidiarrhoeal activity in rodents apparently through protection of endogenous enkephalins and a purely antisecretory mechanism. Its antidiarrhoeal activity in man was assessed in an experimental model of cathartic induced secretory diarrhoea as well as in acute diarrhoea of presumed infectious origin. In six healthy volunteers receiving castor oil and pretreated with acetorphan or placebo in a crossover controlled trial, the drug significantly decreased the number and weight of stools passed during 24 hours. About 200 outpatients with severe acute diarrhoea (more than five stools per day) were included in a randomised double blind study of acetorphan against placebo. The significant antidiarrhoeal activity of acetorphan was established using a variety of criteria: (i) the duration of both diarrhoea and treatment were diminished; (ii) no acetorphan treated patient withdrew from the study whereas five dropped out because of worsening in the placebo group; (iii) the frequency of symptoms associated with diarrhoea--for example, abdominal pain or distension, nausea and anorexia--remaining after two weeks was nearly halved; (iv) using visual analogue scales acetorphan treatment was found more effective than placebo by both investigators and patients. There was statistically no significant difference between acetorphan and placebo in respect of side effects, particularly constipation, which often accompanies the antidiarrhoeal activity of mu opioid receptor agonists this difference is attributable to the lack of antipropulsive activity of acetorphan in man. The efficacy and tolerance of acetorphan suggest that enkephalinase inhibition may represent a novel therapeutic approach for the symptomatic management of acute secretory diarrhoea without impairing intestinal transit.

Fluticasone propionate is a new corticosteroid with low systemic bioavailability. This study reports the outcome of a double blind clinical trial comparing oral fluticasone propionate (5 mg four times daily) with placebo for the treatment of active distal ulcerative colitis. Sixty patients were treated for four weeks, with assessments at two and four weeks. One patient was withdrawn when she was found to have amoebiasis. Thus, results are presented for 29 patients who received placebo and 30 who received fluticasone propionate. The two groups were well matched for age, sex, length of history, and extent of disease. After four weeks of therapy the clinical, sigmoidoscopic, and histological responses were similar in the two groups. It is concluded that fluticasone propionate (5 mg four times daily) is not effective treatment for active distal ulcerative colitis.

To evaluate the impact of food on the efficacy of oral rehydration solution (ORS), a randomised, controlled clinical trial was conducted in 182 adults with cholera. After initial rehydration with an intravenous polyelectrolyte solution for four hours, the patients were randomised to receive one of four rehydration therapies: glucose based ORS and no food for the first 24 hours (group A), glucose based ORS plus food from the beginning of treatment (group B), rice based ORS with no food for the first 24 hours (group C), and rice based ORS plus food from start of therapy (group D). Tetracycline was given after 72 hours to all patients. No significant differences in ORS intake, stool output, and duration of diarrhoea were noted between groups A and B and between groups C and D. A substantial and significant reduction in stool output was, however, shown in the groups who received rice based ORS irrespective of feeding. These results show that food does not potentiate the efficacy of either glucose based or rice based ORS in adults with cholera. Rice based ORS compared with glucose ORS substantially reduces purging in cholera patients.

Although sphincter of Oddi dysfunction is a recognised cause of post cholecystectomy pain, the control mechanisms involved in sphincter of Oddi function are poorly understood. Pharmacological relaxation of the sphincter of Oddi may have a beneficial effect particularly in sphincter of Oddi dysfunction where basal sphincter pressure is high. The aim of this study was to investigate the effects of calcium channel blockade (nicardipine) and synthetic cholecystokinin (ceruletide) on sphincter of Oddi pressures. Nineteen patients (median age 49 years; range 21-75) attending for routine endoscopic retrograde cholangiopancreatographic (ERCP) examination were studied. No patients with evidence of sphincter of Oddi dysfunction were included in the study. Each patient was randomly allocated to receive a three minute intravenous infusion of nicardipine 3 mg (six) ceruletide 5 ng/kg (seven) or placebo (six). Endoscopic biliary manometry was done with recording of basal sphincter of Oddi pressures, sphincter of Oddi phasic wave amplitude and frequency before and after intravenous infusions. In the nicardipine group patients showed a decrease in both basal and phasic amplitude sphincter of Oddi pressure (mm Hg) from the preinfusion values (mean (SEM)) of 24.7 (3.6) and 112.3 (13.4) to 12.9 (2.9) (p less than 0.01) and 89.9 (12.4) (p less than 0.03) after infusion respectively. Ceruletide produced a decrease in sphincter of Oddi phasic wave frequency (c/min) from 3.4 (0.3) before infusion to 2.6 (0.5) after infusion (p less than 0.05). We conclude that nicardipine effectively decreases sphincter of Oddi pressure. This drug may therefore be of value in the treatment of sphincter of Oddi dysfunction where raised sphincter pressures are thought to be the primary pathogenic feature.

The injection of a mixture of ethanolamine oleate and thrombin as an effective treatment for bleeding duodenal ulcer was evaluated in 38 patients entered in a randomised prospective controlled trial. After a one week observation period, 1/19 (5.3%) treated patients and 11/19 (57.9%) control patients had suffered further bleeding (p less than 0.005; CI = 22%-74%). Emergency surgery was required in 1/19 in the treated group compared with 8/19 in the untreated group (CI = 13%-61%; p less than 0.05). The mean (SD) transfusion requirement in the treated group was 1.9 (0.5) U blood compared with 5.3 (0.7) U in the control group. No significant differences related to mortality were detected. In conclusion, local injection therapy is an effective means of haemostasis in patients with bleeding duodenal ulcer who are at risk of further bleeding.

To determine the optimum bile acid regimen for rapid gall stone dissolution, 48 gall stone patients were divided into four groups of 12 according to stone diameter and were randomly allocated to receive one of four treatment regimens: bedtime or mealtime chenodeoxycholic acid (CDCA, 12 mg/kg/day) and bedtime or mealtime ursodeoxycholic acid (UDCA, 12 mg/kg/day). An additional 10 patients treated with a combination of CDCA plus UDCA (each 6 mg/kg/day) at bedtime were matched with the 10 patients on bedtime CDCA and the 10 on bedtime UDCA. The gall stone dissolution rates at six and 12 months were determined by standardised oral cholecystography and expressed as the percentage reduction in the gall stone volume after treatment. The gall stone dissolution rate at six months was higher for UDCA than CDCA treatment (median 78% v 48%, p less than 0.01), and for bedtime than mealtime administration (69% v 39%, p less than 0.02). Both differences were greater for stones less than 8 mm diameter. The dissolution rate was faster for combination therapy than for CDCA alone at both six (82% v 36%, p less than 0.05) and 12 months (100% v 54%, p less than 0.05), but was not different from UDCA alone. We conclude that bile acid treatment should be confined to patients with small gall stones and that bedtime administration of combined UDCA and CDCA is likely to provide the most effective and safe combination.

In a Danish multicentre trial we compared the relapse preventing effects of olsalazine and sulphasalazine in patients with ulcerative colitis over a 12 month treatment period. Two hundred and twenty seven patients (118 men) with at least two previous attacks of ulcerative colitis were randomly allocated according to a prearranged treatment schedule to olsalazine 500 mg bd or sulphasalazine 1 g bd in a double blind, double dummy fashion. One hundred and ninety seven patients completed the trial. The relapse rate after 12 month in the olsalazine group was 46.9% v 42.4% in the sulphasalazine group with a 95% confidence interval for the difference in proportions of -9% to 18%. Seven per cent of the patients were withdrawn from the trial because of adverse drug reactions and these were equally distributed between the two groups.

Fifty nine patients with Helicobacter pylori positive duodenal ulcers that failed to heal after a six week course of treatment with H2 blockers were randomly assigned to one of the following three regimens: (i) bismuth subsalicylate, 600 mg three times daily (n = 19), (ii) ranitidine, 300 mg at night (n = 20), (iii) bismuth subsalicylate plus ranitidine (n = 20). Cumulative ulcer healing rates after four and eight weeks respectively were as follows: bismuth subsalicylate 74% (14/19) and 95% (18/19), ranitidine 40% (8/20) and 65% (13/20), bismuth subsalicylate plus ranitidine 80% (16/20) and 95% (19/20). Bismuth subsalicylate treatment was better than ranitidine at both four and at eight weeks (p less than 0.05). The clearance rates for H pylori after four weeks were: bismuth subsubsalicylate 58%, ranitidine 0%, bismuth subsalicylate plus ranitidine 55%. After stopping bismuth therapy bacterial recrudescence frequently occurred. After bismuth treatment 86% (19/22) of ulcers had healed if H pylori had been cleared, whereas only 65% (11/17) had healed if H pylori persisted (NS). This study shows that bismuth subsalicylate is more effective in the treatment of resistant duodenal ulcers than standard dose ranitidine. It may be that suppression of H pylori by bismuth subsalicylate promotes ulcer healing.

To determine whether an elemental diet or a polymeric defined formula diet would be more effective for treating active Crohn's disease, we conducted a prospective randomised clinical trial in 30 patients with active Crohn's disease unresponsive to steroids and/or complicated by malnutrition. They received a four to six week enteral nutrition course with either an elemental diet or a polymeric diet. Clinical remission occurred in 10 of the 15 patients on elemental diet compared with 11 of the 15 patients assigned to polymeric diet. Both groups showed similar improvements in nutritional status, biological inflammation, alpha 1 antitrypsin clearance, and colonoscopic lesions (diminished in 17 out of 24 patients). Most patients relapsed during the year after discharge. We conclude that enteral nutrition, whatever the diet, is an efficient primary therapy for active Crohn's disease but does not influence the long term outcome.

Altogether, 138 patients were included in a study aimed at evaluating the effect of cisapride on healing and relapse of oesophagitis shown endoscopically. In the first phase of the study cisapride was given in an open fashion at 10 mg four times a day for 8 to 16 weeks, and healing was obtained in 69% of patients. Healing occurred later in patients with grades II to IV oesophagitis. The total score for reflux symptoms decreased by 67%. Eighty of the healed patients were included in the second phase. They were randomly assigned to double blind treatment with either cisapride 10 mg (n = 37) or placebo (n = 43) twice a day. Control endoscopy was performed when symptoms recurred or at the end of the six month trial. The cumulative percentage of patients in remission was higher (p = 0.06, survival analysis) in the cisapride group than in the placebo group, the relapse rates being 20% and 39%. The duration of remission tended to be longer in patients with a lower initial degree of oesophagitis. Adverse effects were no more frequent with cisapride than with placebo. In conclusion, cisapride is efficacious in healing oesophagitis, and, unlike other gastrointestinal prokinetic drugs or low dose cimetidine (400-800 mg daily) or ranitidine (150 mg daily), it may prevent relapse of oesophagitis.

Forty two patients with haemorrhage from peptic ulcers with visible vessels were enrolled in a randomised study comparing endoscopic haemostasis with adrenaline (1:10,000) injections (adrenaline group) and adrenaline injection + neodymium yttrium-aluminium-garnet (Nd:YAG) laser photocoagulation (adrenaline + laser group). The two groups (21 patients each) were well matched for factors affecting outcome. Surgery was performed for continued haemorrhage uncontrolled by endoscopic treatment or rebleeding after two endoscopic treatments. Haemostasis after one treatment was similar in the two groups: adrenaline 16/21 (76%), adrenaline + laser 18/21 (86%). Haemostasis after two treatments was numerically (0.05 less than p less than 0.10) greater in the adrenaline + laser group: 21/21 (100%) v 18/21 (86%). Three patients (14%) in the adrenaline group underwent uneventful emergency surgery. There were no deaths or procedure related complications in either group. Most bleeds from peptic ulcers with visible vessels can be controlled endoscopically without the need for surgery. Both treatments in this study proved highly efficacious in securing haemostasis. Adrenaline injection treatment seems to be the treatment of choice in view of its simplicity, low cost, and availability. Additional Nd:YAG laser treatment may provide a marginal improvement in efficacy, although a much larger trial would be required to prove this.

5-Aminosalicylic acid (5-ASA), the active moiety of sulphasalazine (SASP), was given as a rectal enema to patients with mild to moderate distal ulcerative colitis to determine the minimum effective dosage. A double blind study was carried out using enemas containing 1, 2, or 4 g or 5-ASA or placebo for a one month treatment period. One hundred and thirteen patients with ulcerative colitis attending our outpatient clinic volunteered to participate. Clinical, sigmoidoscopic, and histological assessments were carried out at the beginning of the study and after 15 and 30 days of treatment. All patients who received 5-ASA enemas showed significantly better results than those who received a placebo enema (p less than 0.001) but no difference was detected among the patients receiving differing concentrations of 5-ASA. This study suggests that 1 g 5-ASA (in a 100 ml enema) is a sufficient dosage for patients with a mild to moderate attack of ulcerative colitis.

A new chewable tablet containing cimetidine 200 mg and alginic acid 500 mg, at a dosage of one tablet four times daily, was compared in a 12 week randomised study with the standard dosage of cimetidine (400 mg four times daily) in the management of oesophageal reflux disease. The dose of cimetidine continued unchanged throughout the study but the dose of the combination drugs could be increased after six weeks to two tablets four times a day if response was unsatisfactory. A total of 312 patients had data suitable for analysis. Sixty three per cent of those on the combination tablet completed the study without increasing their dose - that is taking cimetidine equivalent to half the standard dosage used in the control group. The improvement in heartburn symptoms was significantly greater in the combination group than in the group taking full dose cimetidine. There were no significant differences between the treatment groups in healing and improvement of the appearances of oesophagitis after 12 weeks, and healing rates were as expected from previous studies. The addition of alginic acid to cimetidine in this fixed combination tablet is an improvement in symptomatic treatment of oesophageal reflux disease.

One hundred and nine patients presenting with severe haemorrhage from benign peptic ulcers were randomised to either endoscopic injection sclerotherapy using a combination of 1:100,000 adrenaline and 5% ethanolamine or to conservative treatment. Only high risk patients with active bleeding or endoscopic stigmata of recent haemorrhage and accessible ulcers were considered. The two groups were well matched for age, shock, haemoglobin concentration, endoscopic findings, and consumption of non-steroidal anti-inflammatory drugs. The group treated endoscopically had a significantly reduced rebleeding rate (12.5% v 47%, p less than 0.001). Rebleeding was successfully treated in some patients by injection sclerotherapy, other patients underwent urgent surgery. While there was a tendency towards a lower operation rate and lower transfusion requirements in the treated group, this failed to achieve statistical significance. The use of injection sclerotherapy in the conservatively treated group after rebleeding undoubtedly reduced the number of surgical operations. Endoscopic injection sclerotherapy is effective in the prevention of rebleeding in these patients.

A controlled trial was performed to compare enteral feeding with either an amino acid based feed or a whole protein feed as sole treatment for active Crohn's disease. Twenty four patients were studied (nine with ileal, 11 with ileocolonic, and four with colonic disease). Both feeds proved effective; nine of 13 patients randomised to receive the amino acid based feed were in clinical remission within three weeks as defined by a simple activity index compared with eight of 11 treated with the whole protein feed. Patients in clinical remission were then crossed over onto the other feed. None of the six patients who were changed to the whole protein feed relapsed over the subsequent three week period compared with three of seven patients who were changed to the amino acid based feed. In responders the median serum C reactive protein concentration fell from 21 mg/l (range 9-82) on entry to 6 mg/l (range 3-19) at six weeks. Seven patients relapsed within eight months of starting solid food (mean 3.7 months), while nine were still in remission (follow up period 3-9 months, median six months). Detailed studies of staged reintroduction of food and permitted food additives were carried out over a four year period in a patient with extensive stricturing small bowel Crohn's disease who had been brought into remission by open treatment with enteral feeding. Carrageenan, other permitted emulsifiers, bread, meat, potatoes, oranges, refined sugar, dairy produce, flour, and rice were all reintroduced without any objective ill effect, but green vegetables provoked a clinical and biochemical relapse within one week of introduction. Remission was rapidly achieved by switching back to the enteral feed but reintroduction of the low residue diet that had been previously tolerated produced a brisk relapse. Clinical and biochemical remission was again achieved by a return to the enteral feed but relapse again occurred with reintroduction of the low residue diet. These studies confirm the therapeutic effect of enteral feeding in Crohn's disease. This effect does not seem to be due to avoidance of whole protein, but the very low residue of chemically defined enteral feeds may be important, particularly in patients with intestinal strictures.

Twelve healthy volunteers were given one week's oral treatment with each of 300 mg nizatidine, 40 mg famotidine, and placebo once daily in a randomised, placebo controlled, double blind study. Three hours after administration, nizatidine led to a significant reduction in the mean (SD) resting heart rate compared with placebo (63.6 (6.4) beats/minute on placebo to 55.9 (7.2) beats/minute on nizatidine (p less than 0.05)), whereas famotidine did not influence the heart rate significantly. Both drugs, however, increased significantly the pre-ejection period and the ratio of pre-ejection period to left ventricular ejection time on mechanocardiography and led to a significant decrease in cardiac output on impedance cardiography. The exercise heart rate on nizatidine as well as the resting heart rate on concurrent administration of nizatidine and the beta receptor blocking agent atenolol were subsequently investigated in the same volunteers. Nizatidine slightly inhibited exercise tachycardia by 4.4% (p less than 0.05). When compared with placebo, the mean resting heart rate was decreased on atenolol alone by a mean of 10.6 beats/minute (p less than 0.01) and fell further on co-administration with nizatidine to a total of 16.1 beats/minute (p less than 0.05 versus atenolol alone). In conclusion, the effect of nizatidine in reducing the heart rate needs careful evaluation in elderly patients with heart failure or those also taking beta blockers. In contrast to famotidine, long term treatment with 300 mg nizatidine a day has mainly negative chronotropic effects.

Some patients with gastro-oesophageal reflux disease have delayed gastric emptying. This study investigates the effect of cisapride on gastric emptying in 34 patients with proved reflux and delayed gastric emptying of solids. They were enrolled in a double blind controlled crossover study. Placebo or cisapride (10 mg) tablets were given three times a day for three days followed by further assessment of gastric emptying. The protocol was repeated with the crossover tablet. Gastric emptying was assessed by a dual radionuclide technique. The percentage of a solid meal remaining in the stomach at 100 minutes (% R100 minutes) and the time taken for 50% of the liquid to empty (T50 minutes) were calculated and analysed by the Wilcoxon matched pairs signed ranks test and expressed as medians (ranges). For gastric emptying of solids the initial % R100 minutes (70 (60-100)%) was not significantly different from placebo (71 (35-100)%). After cisapride treatment a significant acceleration (p less than 0.001) in gastric emptying occurred (% R100 minutes, 50.5 (28-93)%). Similarly with gastric emptying of liquids, the initial T50 minute value was 26.5 (12-82) minutes, after placebo the value was 28 (11-81) minutes, but this was significantly accelerated with cisapride (p less than 0.03) to 22.5 (6-61) minutes. The acceleration in gastric emptying occurred in the proximal portion of the stomach for gastric emptying of both solids and liquids suggesting that this is the principal site of action of cisapride. We conclude that cisapride significantly accelerates gastric emptying of both solids and liquids in patients with gastro-oesophageal reflux disease and delayed gastric emptying.

The ability of hypnosis to modulate the orocaecal transit time of 10 g lactulose was tested in six healthy volunteers. Orocaecal transit time was measured by the hydrogen breath test during three periods in random order. During the control period the subjects remained throughout the test in a semirecumbent position without moving. During the hypnotic relaxation period subjects were hypnotised before lactulose ingestion and were instructed to experience relaxation till the orocaecal transit time had elapsed. During the acceleration suggestion period subjects were hypnotised before lactulose ingestion and were repeatedly instructed to imagine the acceleration of lactulose through the intestine until transit time had elapsed. The mean orocaecal transit time was significantly longer during the hypnotic relaxation period (mean (SEM) 133 (8) min) than during the control period (93 (13) min). The mean orocaecal transit time during the acceleration suggestion period was 105 (26) minutes and was not significantly different from the mean transit time during the control period. The individual values during the acceleration suggestion period were scattered. We conclude that lactulose orocaecal transit time is delayed during hypnotic relaxation.

We tested the hypothesis that the gastric H+/K+ adenosine triphosphatase inhibitor, omeprazole, because of its different mode of action and pronounced inhibitory effect on gastric acid secretion, may be more effective in peptic ulcer that is refractory to histamine H2 receptor antagonist treatment than continuing the same therapy. Altogether 107 patients (duodenal ulcer, n = 88; prepyloric ulcer, n = 14; gastric ulcer, n = 3; mixed sites, n = 2) with refractory peptic ulcer - that is ulcer unhealed after at least two months' treatment with cimetidine 0.8 g or 1 g daily or with ranitidine 0.3 g daily - were randomly allocated to receive either omeprazole 40 mg daily (n = 54) or to continue treatment with the same H2 receptor antagonist and at the same dose (n = 53) for up to eight weeks. The patients in the two treatment groups were well matched demographically. Healing by 'intent to treat' analysis was as follows: at four weeks, omeprazole 46 of 54 (85%), H2 receptor antagonist 18 of 53 (34%) (p less than 0.0001); and at eight weeks, 52 of 54 (96%) and 30 of 53 (57%) respectively (p less than 0.0001). One patient was lost to follow up but of the 22 patients whose ulcers were shown to be unhealed at endoscopy after receiving continued H2 receptor antagonist treatment, 21 healed in four to eight weeks when changed to omeprazole. Daytime epigastric pain cleared at four weeks in 43 of 47 (91%) patients on omeprazole and in 32 of 46 (70%) on H2 receptor antagonists (p=0.01) and relief of all dyspeptic symptoms occurred in 39 of 47 (83%) and 23 of 45 (51%) (p=0.0009) patients respectively. Adverse events occurred in 11 of 54 (20%) patients on omeprazole and in 12 of 35 (34%) on cimetidine but in none on ranitidine. The events were mild and none required treatment withdrawal. The commonest event in patients on omeprazole was loose stools or diarrhoea (n=5). Omeprazole was significantly better than continued H2 receptor antagonist treatment for the short term management of refractory peptic ulcer as judged by healing rate and pain relief, and it was safe.